Chemoradiotherapy is an important treatment paradigm in cancer management. Given its importance, one of the primary research objectives in oncology has been to develop agents to further improve chemoradiotherapy's therapeutic index. One class of agent, the DNA repair inhibitors (DRIs), holds high potential in such application. However, DRIs' clinical translation has been prevented by drug delivery challenges. While traditional drug delivery methods have been unable to overcome these challenges, the development of nanoparticle (NP) drug delivery vehicles offers an unprecedented opportunity. NPs' preferential accumulation in tumors, low distribution in normal tissue, and controlled release properties are all favorable characteristics for applications in chemoradiotherapy. Our group was the first to develop an NP DRI, NP wortmannin (Wtmn), and demonstrated its potential in improving radiotherapy. We are also one of the first to demonstrate that NP therapeutics are more effective than their small molecule counterparts in chemoradiotherapy. We hypothesize that NP delivery can overcome the drug delivery challenges and facilitate the clinical translation of DRIs in chemoradiotherapy. The overall objective of this application is to develop and evaluate NP DRIs for chemoradiotherapy. To engineer NP DRIs, we plan to utilize the Particle Replication in Non-Wetting Templates (PRINT) NP platform, which is capable of fabricating NPs with precise control over size, shape, drug loading and drug release. Importantly, PRINT has undergone the clinical development process, which will enhance rapid clinical translation. Head and neck squamous cell carcinoma (HNSCC) will be used as a model disease since chemoradiotherapy is the most common and effective treatment for this disease. Our application has three specific aims. The first aim will focus on understanding and optimizing the key factors, such as drug release, that can affect PRINT NP Wtmn's efficacy and toxicity. Our second aim will study to the extent which co-delivering a chemotherapeutic with Wtmn can improve chemoradiotherapy. We aim to engineer PRINT NPs that can either co-deliver docetaxel or cisplatin, two mostly commonly used chemotherapeutics in HNSCC, with Wtmn. These NPs will be evaluated in mouse models of HNSCC and compared to chemotherapy and NP Wtmn given separately. The third aim will study NP formulations of poly ADP ribose polymerase inhibitors (PARPIs)'s potential in chemoradiotherapy. PARPIs are DRIs and are known to act synergistically with both chemotherapy and radiotherapy. Such dual sensitization provides them unique potentials in chemoradiotherapy. In summary, our application aims to apply advances in nanomedicine to improving chemoradiotherapy. Our work can lead to the rapid clinical development of NP DRIs for chemoradiotherapy. It can directly translate into increased cure rates and improved survival in patients with HNSCC and other difficult to treat cancers. My long term research goal is to utilize develop and utilize NP therapeutics, such as DRIs, to improve the chemoradiotherapy treatment paradigm.